An injection containing meropenem and its preparation method

Abstract

The present invention belongs to the field of pharmaceutical preparations involving antibiotics, and in particular to an injection containing meropenem and a preparation method thereof. The present invention uses 4-sulfonic acid calixarene to modify the surface of nano calcium carbonate, and the obtained carrier complex can enhance the solubility of meropenem, and has a high specific surface area and strong adsorption capacity, does not produce toxicity, and does not induce the body's immune response; stevioside, rosmarinic acid and albumin solution are mixed, and cysteine ​​is used to reduce the disulfide bonds of albumin. The protective composition obtained by freeze spray drying can effectively repair damaged tissues; the meropenem-containing mixed solution undergoes a precipitation reaction, and the protective composition, 0.9% sodium chloride solution, and sterile water for injection are mixed by centrifugation and filtration. The prepared meropenem-containing injection has strong stability, does not induce allergic reactions in the body, reduces the irritation of meropenem to body tissues, and does not require multiple injections.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations involving antibiotics, and specifically refers to an injection containing meropenem and a preparation method thereof. Background Art

[0002] Meropenem is a broad-spectrum, potent antibiotic belonging to the carbapenem antibiotic family. It exerts its antibacterial effect by inhibiting the synthesis of bacterial cell walls and has strong antibacterial activity against a variety of Gram-positive and Gram-negative bacteria. Meropenem injection is widely used to treat various infections caused by sensitive bacteria due to its broad antibacterial spectrum and high antibacterial ability. Meropenem injection has antibacterial effects on a variety of bacteria including Pseudomonas aeruginosa, and can effectively treat infections including pneumonia, urinary tract infections, gynecological infections, skin and soft tissue infections, meningitis, and sepsis.

[0003] Meropenem injection can be used alone or in combination with other antibiotics to treat multiple infections. Meropenem injection is usually administered intravenously to ensure rapid and effective drug concentrations. The dose used depends on the severity and type of infection. In the treatment of meningitis, a higher amount of Meropenem injection is required.

[0004] At present, the existing meropenem injection preparation technology has the following problems: First, after intravenous injection of meropenem injection, the body will experience severe allergic reactions such as rash and skin itching; second, meropenem injection will irritate the kidneys and gastrointestinal tract after injection, causing damage; third, when the existing meropenem injection is used for long-term high-dose treatment, the cationic liposomes used will be highly toxic to the body, and after long-term injection, bacteria insensitive to meropenem will grow too fast, affecting the balance of the body's flora. Summary of the invention

[0005] In view of the above situation, in order to overcome the defects of the prior art, the present invention provides an injection containing meropenem and a preparation method thereof. In order to solve the problems of allergic reactions in the body after injection of the existing injection containing meropenem, irritation to the kidneys and gastrointestinal tract, and the need for long-term injections that affect the balance of the body's flora, the present invention uses a meropenem mixed carrier complex and a protective composition. The prepared injection containing meropenem has strong stability, will not induce allergic reactions in the body, has extremely low irritation to body tissues, does not require multiple injections, and protects the balance of the body's flora.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows: the present invention proposes an injection containing meropenem, and the raw materials for preparing the injection containing meropenem specifically include the following components in parts by weight:

[0007] 10-13 parts of meropenem, 25-30 parts of carrier complex, 18-23 parts of protective composition, 25-35 parts of 0.9% sodium chloride solution, 10-12 parts of sodium carboxymethyl cellulose, and 2000-2600 parts of sterile water for injection.

[0008] Preferably, the raw materials for preparing the carrier complex include the following components in parts by weight: 30-50 parts of 4-sulfonic acid calixarene and 40-60 parts of nano calcium carbonate; the raw materials for preparing the protective composition include the following components in parts by weight: 25-35 parts of stevioside, 30-40 parts of rosmarinic acid, 40-46 parts of albumin, and 25-35 parts of cysteine; the albumin was purchased from Sigma with the catalog number A5503.

[0009] Preferably, the method for preparing the carrier complex specifically comprises the following steps:

[0010] S1. Dissolve 4-sulfonic acid calixarene in ultrapure water, put into a stirrer with a power of 1.2-1.6 kW, stir at a temperature of 25-30° C., stir for 10-15 min, stir at a speed of 120-140 r / min, and stir evenly to obtain a 4-sulfonic acid calixarene solution;

[0011] S2, dispersing nano calcium carbonate in anhydrous ethanol, placing in an ultrasonic stirrer with a power of 1.8-2.5 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20000 r / min, a stirring temperature of 25-30° C., and a stirring time of 10-15 min to form a nano calcium carbonate suspension;

[0012] S3, putting the nano calcium carbonate suspension prepared by S2 into the 4-sulfonic acid calixarene solution prepared by S1, stirring at a temperature of 25-30°C, stirring for 10-13 min, stirring at a speed of 180-200 r / min, and after mixing evenly, adjusting the pH to 7.5 with a 30% mass fraction sodium hydroxide solution, putting it into a reactor with a power of 2.2-2.6 kW, reacting at a temperature of 65-75°C, reacting for 1.5-2.5 h, and reacting at a speed of 260-280 r / min, and obtaining a carrier complex solution after the reaction;

[0013] S4. Place the carrier complex solution prepared in S3 into a vacuum dryer with a power of 1.6-2.2 kW, a vacuum drying pressure of 0.3 MPa, a vacuum drying temperature of 55-60°C, and a vacuum drying time of 4 h. After vacuum drying, a carrier complex is obtained.

[0014] Furthermore, in step S1, the mass fraction of the 4-sulfonic acid calixarene in ultrapure water is 25%-50%; in step S2, the mass fraction of the nano-calcium carbonate in anhydrous ethanol is 33%-60%.

[0015] Preferably, the method for preparing the protective composition specifically comprises the following steps:

[0016] L1. Dissolve stevioside and rosmarinic acid in ultrapure water, put into a stirrer with a power of 1.2-1.6 kW, stir at a temperature of 23-26°C, stir for 10-15 min, stir at a speed of 110-130 r / min, mix well, and obtain a mixed solution;

[0017] L2. Dissolve albumin in ultrapure water, put into a stirrer with a power of 1.2-1.6 kW, stir at a temperature of 20-28°C, stir for 15-18 min, stir at a speed of 150-180 r / min, and mix well to obtain an albumin solution;

[0018] L3. Put the mixed solution prepared by L1 into the albumin solution prepared by L2, with a stirring temperature of 20-28°C, a stirring time of 20-25 min, and a stirring speed of 150-180 r / min. After mixing evenly, put it into a reactor with a power of 2.2-2.6 kW with cysteine, and the reaction temperature is 80°C. The reaction time is 2-2.5 h and the reaction speed is 230-260 r / min. After the reaction, put it into a vacuum freeze-nano spray dryer with a power of 2.3-2.8 kW, the vacuum degree is -0.05 MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, and the freeze-nano spray drying time is 2.5-3 h to obtain a protective composition.

[0019] Furthermore, in step L1, the mass fraction of stevioside in ultrapure water is 10%-15%, and the mass fraction of rosmarinic acid in ultrapure water is 12%-18%; in step L2, the mass fraction of albumin in ultrapure water is 4%-5%.

[0020] The present invention also provides a method for preparing an injection containing meropenem, which specifically comprises the following steps:

[0021] Step 1, weigh 220-240 parts by weight of chloroform-anhydrous ethanol and meropenem, carrier complex, and sodium carboxymethyl cellulose, put them into a stirrer with a power of 1.2-1.6 kW, stir at a temperature of 20-28° C., stir for 25-30 min, and stir at a speed of 120-150 r / min, fully dissolve them, and obtain a mixed solution containing meropenem;

[0022] Step 2: The meropenem-containing mixed solution prepared in step 1 is adjusted to a pH value of 8.0-8.5 using a 5 mol / L sodium carbonate solution, and then placed in a reactor with a power of 2.2-2.6 kW, with a reaction stirring rate of 1000-1300 r / min, a reaction temperature of 70-95°C, a reaction time of 70-90 min, and a precipitation reaction is performed to obtain a drug-containing nanoparticle suspension;

[0023] Step 3, placing the drug-containing nanoparticle suspension prepared in step 2 into a high-speed centrifuge with a power of 2.6-2.9 kW, the centrifugal speed is 12000-14000 r / min, the centrifugal temperature is 2°C, the centrifugal time is 10-15 min, and after centrifugation, it is placed at 28°C for 1-1.5 h, and filtered using a sterile filter with a pore size of 100 nm to obtain drug-containing nanoparticles;

[0024] Step 4. Place the drug-containing nanoparticles prepared in step 3, the protective composition, 0.9% sodium chloride solution, and sterile water for injection into a stirrer with a power of 1.2-1.6 kW, the stirring temperature is 20-28°C, the stirring time is 18-26 min, the stirring speed is 100-130 r / min, and after mixing, filter using a 0.22 mm sterile filter membrane to obtain an injection containing meropenem.

[0025] The beneficial effects achieved by the present invention are as follows:

[0026] The invention adopts 4-sulfonic acid calixarene to carry out surface modification on nano calcium carbonate. The sulfonic acid group contained in the 4-sulfonic acid calixarene is a strong polar group with high electronegativity. The sulfonic acid group can release hydrogen ions to form sulfonate ions. Water molecules can form hydrogen bonds with these ions to enhance solubility. The 4-sulfonic acid calixarene is non-toxic and does not induce immune response of the body. The 4-sulfonic acid calixarene solution is mixed with the nano calcium carbonate suspension, and the sulfonic acid group of the sulfonic acid calixarene forms a coordination bond with the calcium ions on the surface of the nano calcium carbonate to achieve surface modification. The obtained carrier complex has high specific surface area, strong adsorption capacity, is non-toxic and is not easy to cause allergic reaction. Stevioside and rosmarinic acid are mixed to prepare an anti-inflammatory solution, which is mixed with an albumin solution. , using cysteine ​​to reduce the disulfide bonds of albumin, promoting albumin self-assembly to form nanoparticles, and then freeze-spray drying to obtain a protective composition, which can be targeted and combined with cyclooxygenase 2 secreted by the kidney and gastrointestinal tissues of the organism, so that the rosmarinic acid and stevioside in the protective combination can reach the damaged tissue more efficiently, reducing the damage of meropenem to the kidney and gastrointestinal tract. The albumin nanoparticles are small, have a large specific surface area, and have good biocompatibility. They can effectively load stevioside and rosmarinic acid to repair tissues, and cooperate with meropenem to produce better therapeutic effects; meropenem, carrier complex, and sodium carboxymethyl cellulose are stirred evenly and dissolved in chloroform-anhydrous ethanol, so that the carrier complex can fully adsorb meropenem. The concentration used is 5 The pH value is adjusted with a 0.1% mol / L sodium carbonate solution to cause a precipitation reaction. The drug-containing nanoparticles obtained by high-speed centrifugation and filtration are mixed with a protective composition, a 0.9% sodium chloride solution, and sterile water for injection. The prepared meropenem-containing injection has strong stability and is not easy to cause allergic reactions in the body. Meropenem has strong solubility and can target and repair damaged kidneys and gastrointestinal tissues, reduce the irritation of meropenem to body tissues, and the effective components in the injection can exert their effects for a long time due to their efficient drug loading, sustained release, and rapid efficacy. There is no need for multiple injections to protect the balance of the flora in the body. The meropenem-containing injection of the present invention can also adopt advanced powder-liquid double-chamber bag dosage form technology, and the prepared drug-containing nanoparticles, protective composition, 0.9% sodium chloride solution, and sterile water for injection are packed in an independent double-chamber structure to further ensure drug stability and ease of use. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the present invention or the technical solutions in the prior art, the following will be described in a clear and understandable manner in conjunction with the accompanying drawings. Obviously, the drawings described below are only for the present invention, and for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0028] Figure 1This is a graph showing the results of the sensitization ability test described in Experimental Example 1 of the present invention;

[0029] Figure 2 This is the staining image of the kidney tissue of the rats in the control group described in Experimental Example 2 of the present invention (×500);

[0030] Figure 3 This is the staining image of the kidney tissue of rats in the comparative example 2 described in the experimental example 2 of the present invention (×500);

[0031] Figure 4 This is the staining image of the rat kidney tissue of Example 1 group described in Experimental Example 2 of the present invention (×500);

[0032] Figure 5 This is a graph showing the results of the recovery of rats as described in Experimental Example 3 of the present invention. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0034] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only and are not intended to limit the content of this application.

[0035] The experimental methods in the following examples are conventional methods unless otherwise specified; the experimental materials and test strains used in the following examples are purchased from commercial channels unless otherwise specified.

[0036] Example 1: This example provides an injection containing meropenem and a preparation method thereof. The injection containing meropenem comprises the following components in parts by weight:

[0037] 10 parts of meropenem, 25 parts of carrier complex, 18 parts of protective composition, 25 parts of 0.9% sodium chloride solution, 10 parts of sodium carboxymethyl cellulose, and 2000 parts of sterile water for injection.

[0038] The raw materials for preparing the carrier complex include the following components in parts by weight: 30 parts of 4-sulfonic acid calixarene and 40 parts of nano calcium carbonate; the raw materials for preparing the protective composition include the following components in parts by weight: 25 parts of stevioside, 30 parts of rosmarinic acid, 40 parts of albumin, and 25 parts of cysteine; the albumin was purchased from Sigma with a product number of A5503.

[0039] The method for preparing the carrier complex specifically comprises the following steps:

[0040] S1. Dissolve 4-sulfonic acid calixarene in ultrapure water, put into a stirrer with a power of 1.2 kW, stir at a temperature of 25°C, stir for 10 min, stir at a speed of 120 r / min, and stir evenly to obtain a 4-sulfonic acid calixarene solution;

[0041] S2, dispersing nano-calcium carbonate in anhydrous ethanol, placing in an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 25° C., and a stirring time of 10 min to form a nano-calcium carbonate suspension;

[0042] S3, the nano-calcium carbonate suspension prepared by S2 was placed in the 4-sulfonic acid calixarene solution prepared by S1, the stirring temperature was 25°C, the stirring time was 10 min, the stirring speed was 180 r / min, after mixing evenly, the pH was adjusted to 7.5 with a 30% mass fraction of sodium hydroxide solution, and the suspension was placed in a reactor with a power of 2.2 kW, the reaction temperature was 65°C, the reaction time was 1.5 h, the reaction speed was 260 r / min, and the carrier complex solution was obtained after the reaction;

[0043] S4. Place the carrier complex solution prepared in S3 into a vacuum dryer with a power of 1.6 kW, the vacuum drying pressure is 0.3 MPa, the vacuum drying temperature is 55° C., the vacuum drying time is 4 h, and after vacuum drying, a carrier complex is obtained.

[0044] In step S1, the mass fraction of the 4-sulfonic acid calixarene in ultrapure water is 25%; in step S2, the mass fraction of the nano-calcium carbonate in anhydrous ethanol is 33%.

[0045] The preparation method of the protective composition specifically comprises the following steps:

[0046] L1. Dissolve stevioside and rosmarinic acid in ultrapure water, put into a 1.2 kW stirrer, stir at 23°C, stir for 10 min, stir at 110 r / min, mix well, and obtain a mixed solution;

[0047] L2. Dissolve albumin in ultrapure water, put it into a stirrer with a power of 1.2 kW, stir at a temperature of 20°C, stir for 15 min, stir at a speed of 150 r / min, and mix well to obtain an albumin solution;

[0048] L3. Put the mixed solution prepared by L1 into the albumin solution prepared by L2, with a stirring temperature of 20°C, a stirring time of 20 min, and a stirring speed of 150 r / min. After mixing evenly, put it into a reactor with a power of 2.2 kW with cysteine, and the reaction temperature is 80°C, the reaction time is 2 h, and the reaction speed is 230 r / min. After the reaction, put it into a vacuum freeze-nano spray dryer with a power of 2.3 kW, the vacuum degree is -0.05 MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, and the freeze-nano spray drying time is 2.5 h to obtain a protective composition.

[0049] In step L1, the mass fraction of stevioside in ultrapure water is 10%, and the mass fraction of rosmarinic acid in ultrapure water is 12%; in step L2, the mass fraction of albumin in ultrapure water is 4%.

[0050] This embodiment also provides a method for preparing an injection containing meropenem, which specifically comprises the following steps:

[0051] Step 1, weigh 220 parts by weight of chloroform-anhydrous ethanol and meropenem, carrier complex, and sodium carboxymethyl cellulose, put them into a stirrer with a power of 1.2 kW, stir at a temperature of 20° C., stir for 25 min, and stir at a speed of 120 r / min, fully dissolve them, and obtain a mixed solution containing meropenem;

[0052] Step 2: The meropenem-containing mixed solution prepared in step 1 was adjusted to a pH value of 8.0 using a 5 mol / L sodium carbonate solution, and then placed in a reactor with a power of 2.2 kW, with a reaction stirring rate of 1000 r / min, a reaction temperature of 70°C, and a reaction time of 70 min to obtain a drug-containing nanoparticle suspension after a precipitation reaction;

[0053] Step 3: Place the drug-containing nanoparticle suspension prepared in step 2 into a high-speed centrifuge with a power of 2.6 kW, the centrifugal speed is 12000 r / min, the centrifugal temperature is 2°C, the centrifugal time is 10 min, and after centrifugation, place it at 28°C for 1 h, and filter it using a sterile filter with a pore size of 100 nm to obtain drug-containing nanoparticles;

[0054] Step 4: Place the drug-containing nanoparticles prepared in step 3, the protective composition, 0.9% sodium chloride solution, and sterile water for injection into a 1.2 kW stirrer at a stirring temperature of 20°C, a stirring time of 18 min, and a stirring speed of 100 r / min. After mixing, filter using a 0.22 mm sterile filter membrane to obtain an injection containing meropenem.

[0055] Example 2: This example provides an injection containing meropenem and a preparation method thereof. The injection containing meropenem comprises the following components in parts by weight:

[0056] 12 parts of meropenem, 28 parts of carrier complex, 21 parts of protective composition, 30 parts of 0.9% sodium chloride solution, 11 parts of sodium carboxymethyl cellulose, and 2300 parts of sterile water for injection.

[0057] The raw materials for preparing the carrier complex include the following components in parts by weight: 40 parts of 4-sulfonic acid calixarene and 50 parts of nano calcium carbonate; the raw materials for preparing the protective composition include the following components in parts by weight: 30 parts of stevioside, 35 parts of rosmarinic acid, 43 parts of albumin, and 30 parts of cysteine; the albumin was purchased from Sigma with a product number of A5503.

[0058] The method for preparing the carrier complex specifically comprises the following steps:

[0059] S1. Dissolve 4-sulfonic acid calixarene in ultrapure water, put into a stirrer with a power of 1.4 kW, stir at a temperature of 28°C, stir for 13 min, stir at a speed of 130 r / min, and stir evenly to obtain a 4-sulfonic acid calixarene solution;

[0060] S2, dispersing nano-calcium carbonate in anhydrous ethanol, placing in an ultrasonic stirrer with a power of 2.2 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 28° C., and a stirring time of 13 min to form a nano-calcium carbonate suspension;

[0061] S3, the nano calcium carbonate suspension prepared by S2 was placed in the 4-sulfonic acid calixarene solution prepared by S1, the stirring temperature was 28 ° C, the stirring time was 12 min, the stirring speed was 190 r / min, after mixing evenly, the pH was adjusted to 7.5 with a 30% mass fraction of sodium hydroxide solution, and the suspension was placed in a reactor with a power of 2.4 kW, the reaction temperature was 70 ° C, the reaction time was 2 h, the reaction speed was 270 r / min, and the carrier complex solution was obtained after the reaction;

[0062] S4. Put the carrier complex solution prepared in S3 into a vacuum dryer with a power of 1.9 kW, the vacuum drying pressure is 0.3 MPa, the vacuum drying temperature is 58°C, the vacuum drying time is 4 h, and after vacuum drying, a carrier complex is obtained.

[0063] In step S1, the mass fraction of the 4-sulfonic acid calixarene in ultrapure water is 35%; in step S2, the mass fraction of the nano-calcium carbonate in anhydrous ethanol is 45%.

[0064] The preparation method of the protective composition specifically comprises the following steps:

[0065] L1. Dissolve stevioside and rosmarinic acid in ultrapure water, put into a 1.4 kW stirrer, stir at 25°C, stir for 13 min, stir at 120 r / min, mix well, and obtain a mixed solution;

[0066] L2. Dissolve albumin in ultrapure water, put it into a stirrer with a power of 1.4 kW, stir at a temperature of 24°C, stir for 17 min, stir at a speed of 160 r / min, and mix well to obtain an albumin solution;

[0067] L3. Put the mixed solution prepared by L1 into the albumin solution prepared by L2, with a stirring temperature of 24°C, a stirring time of 23 min, and a stirring speed of 170 r / min. After mixing evenly, put it into a reactor with a power of 2.4 kW with cysteine, and the reaction temperature was 80°C, the reaction time was 2.3 h, and the reaction speed was 250 r / min. After the reaction, put it into a vacuum freeze-nano spray dryer with a power of 2.6 kW, the vacuum degree was -0.05 MPa, the freeze-nano spray drying temperature was -40°C, the freeze-nano spray drying particle size was 100 nm, and the freeze-nano spray drying time was 2.8 h to obtain a protective composition.

[0068] In step L1, the mass fraction of stevioside in ultrapure water is 13%, and the mass fraction of rosmarinic acid in ultrapure water is 15%; in step L2, the mass fraction of albumin in ultrapure water is 4%.

[0069] This embodiment also provides a method for preparing an injection containing meropenem, which specifically comprises the following steps:

[0070] Step 1, weigh 230 parts by weight of chloroform-anhydrous ethanol and meropenem, carrier complex, and sodium carboxymethyl cellulose, put them into a stirrer with a power of 1.4 kW, stir at a temperature of 24° C., stir for 28 min, and stir at a speed of 140 r / min, fully dissolve them, and obtain a mixed solution containing meropenem;

[0071] Step 2: The meropenem-containing mixed solution prepared in step 1 was adjusted to a pH value of 8.3 using a 5 mol / L sodium carbonate solution, and then placed in a reactor with a power of 2.4 kW, with a reaction stirring rate of 1200 r / min, a reaction temperature of 85°C, and a reaction time of 80 min to obtain a drug-containing nanoparticle suspension after a precipitation reaction;

[0072] Step 3: Place the drug-containing nanoparticle suspension prepared in step 2 into a high-speed centrifuge with a power of 2.8 kW, the centrifugal speed is 13000 r / min, the centrifugal temperature is 2°C, the centrifugal time is 13 min, and after centrifugation, place it at 28°C for 1.3 h, and filter it using a sterile filter with a pore size of 100 nm to obtain drug-containing nanoparticles;

[0073] Step 4: Place the drug-containing nanoparticles prepared in step 3, the protective composition, 0.9% sodium chloride solution, and sterile water for injection into a 1.4 kW stirrer at a stirring temperature of 24°C, a stirring time of 22 min, and a stirring speed of 120 r / min. After mixing, filter using a 0.22 mm sterile filter membrane to obtain an injection containing meropenem.

[0074] Example 3: This example provides an injection containing meropenem and a preparation method thereof. The injection containing meropenem comprises the following components in parts by weight:

[0075] 13 parts of meropenem, 30 parts of carrier complex, 23 parts of protective composition, 35 parts of 0.9% sodium chloride solution, 12 parts of sodium carboxymethyl cellulose, and 2600 parts of sterile water for injection.

[0076] The raw materials for preparing the carrier complex include the following components in parts by weight: 50 parts of 4-sulfonic acid calixarene and 60 parts of nano calcium carbonate; the raw materials for preparing the protective composition include the following components in parts by weight: 35 parts of stevioside, 40 parts of rosmarinic acid, 46 parts of albumin, and 35 parts of cysteine; the albumin was purchased from Sigma with a product number of A5503.

[0077] The method for preparing the carrier complex specifically comprises the following steps:

[0078] S1. Dissolve 4-sulfonic acid calixarene in ultrapure water, put into a stirrer with a power of 1.6 kW, stir at a temperature of 30°C, stir for 15 min, stir at a speed of 140 r / min, and stir evenly to obtain a 4-sulfonic acid calixarene solution;

[0079] S2, dispersing nano-calcium carbonate in anhydrous ethanol, placing in an ultrasonic stirrer with a power of 2.5 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 30° C., and a stirring time of 15 min to form a nano-calcium carbonate suspension;

[0080] S3, the nano calcium carbonate suspension prepared by S2 is placed in the 4-sulfonic acid calixarene solution prepared by S1, the stirring temperature is 30°C, the stirring time is 13 min, the stirring speed is 200 r / min, after mixing evenly, the pH is adjusted to 7.5 with a 30% mass fraction sodium hydroxide solution, and the suspension is placed in a reactor with a power of 2.6 kW, the reaction temperature is 75°C, the reaction time is 2.5 h, the reaction speed is 280 r / min, and the carrier complex solution is obtained after the reaction;

[0081] S4. Put the carrier complex solution prepared in S3 into a vacuum dryer with a power of 2.2 kW, the vacuum drying pressure is 0.3 MPa, the vacuum drying temperature is 60°C, the vacuum drying time is 4 h, and after vacuum drying, a carrier complex is obtained.

[0082] In step S1, the mass fraction of the 4-sulfonic acid calixarene in ultrapure water is 50%; in step S2, the mass fraction of the nano-calcium carbonate in anhydrous ethanol is 60%.

[0083] The preparation method of the protective composition specifically comprises the following steps:

[0084] L1. Dissolve stevioside and rosmarinic acid in ultrapure water, put into a 1.6 kW stirrer, stir at 26°C, stir for 15 min, stir at 130 r / min, mix well, and obtain a mixed solution;

[0085] L2. Dissolve albumin in ultrapure water, put it into a stirrer with a power of 1.6 kW, stir at a temperature of 28°C, stir for 18 min, stir at a speed of 180 r / min, and mix well to obtain an albumin solution;

[0086] L3. Put the mixed solution prepared by L1 into the albumin solution prepared by L2, with a stirring temperature of 28°C, a stirring time of 25 min, and a stirring speed of 180 r / min. After mixing evenly, put it into a reactor with a power of 2.6 kW with cysteine, and the reaction temperature was 80°C, the reaction time was 2.5 h, and the reaction speed was 260 r / min. After the reaction, put it into a vacuum freeze-nano spray dryer with a power of 2.8 kW, the vacuum degree was -0.05 MPa, the freeze-nano spray drying temperature was -40°C, the freeze-nano spray drying particle size was 100 nm, and the freeze-nano spray drying time was 3 h to obtain a protective composition.

[0087] In step L1, the mass fraction of stevioside in ultrapure water is 15%, and the mass fraction of rosmarinic acid in ultrapure water is 18%; in step L2, the mass fraction of albumin in ultrapure water is 5%.

[0088] This embodiment also provides a method for preparing an injection containing meropenem, which specifically comprises the following steps:

[0089] Step 1, weigh 240 parts by weight of chloroform-anhydrous ethanol, meropenem, carrier complex, and sodium carboxymethyl cellulose, put them into a stirrer with a power of 1.6 kW, stir at a temperature of 28° C., stir for 30 min, and stir at a speed of 150 r / min, fully dissolve them, and obtain a mixed solution containing meropenem;

[0090] Step 2: The meropenem-containing mixed solution prepared in step 1 was adjusted to a pH value of 8.5 using a 5 mol / L sodium carbonate solution, and then placed in a reactor with a power of 2.6 kW, with a reaction stirring rate of 1300 r / min, a reaction temperature of 95°C, and a reaction time of 90 min to obtain a drug-containing nanoparticle suspension after a precipitation reaction;

[0091] Step 3: Place the drug-containing nanoparticle suspension prepared in step 2 into a high-speed centrifuge with a power of 2.9 kW, the centrifugal speed is 14000 r / min, the centrifugal temperature is 2°C, the centrifugal time is 15 min, and after centrifugation, place it at 28°C for 1.5 h, and filter it using a sterile filter with a pore size of 100 nm to obtain drug-containing nanoparticles;

[0092] Step 4: Place the drug-containing nanoparticles prepared in step 3, the protective composition, 0.9% sodium chloride solution, and sterile water for injection into a 1.6 kW stirrer at a stirring temperature of 28°C, a stirring time of 26 min, and a stirring speed of 130 r / min. After mixing, filter using a 0.22 mm sterile filter membrane to obtain an injection containing meropenem.

[0093] Example 4: This example provides an injection containing meropenem and a preparation method thereof. The injection containing meropenem comprises the following components in parts by weight:

[0094] 11 parts of meropenem, 26 parts of carrier complex, 20 parts of protective composition, 28 parts of 0.9% sodium chloride solution, 11 parts of sodium carboxymethyl cellulose, and 2100 parts of sterile water for injection.

[0095] The raw materials for preparing the carrier complex include the following components in parts by weight: 35 parts of 4-sulfonic acid calixarene and 45 parts of nano calcium carbonate; the raw materials for preparing the protective composition include the following components in parts by weight: 28 parts of stevioside, 32 parts of rosmarinic acid, 42 parts of albumin, and 28 parts of cysteine; the albumin was purchased from Sigma with a product number of A5503.

[0096] The method for preparing the carrier complex specifically comprises the following steps:

[0097] S1. Dissolve 4-sulfonic acid calixarene in ultrapure water, put into a stirrer with a power of 1.3 kW, stir at a temperature of 26°C, stir for 12 min, stir at a speed of 120 r / min, and stir evenly to obtain a 4-sulfonic acid calixarene solution;

[0098] S2, dispersing nano-calcium carbonate in anhydrous ethanol, placing in an ultrasonic stirrer with a power of 1.9 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 27° C., and a stirring time of 12 min to form a nano-calcium carbonate suspension;

[0099] S3, the nano calcium carbonate suspension prepared by S2 was placed in the 4-sulfonic acid calixarene solution prepared by S1, the stirring temperature was 26 ° C, the stirring time was 11 min, the stirring speed was 180 r / min, after mixing evenly, the pH was adjusted to 7.5 with a 30% mass fraction of sodium hydroxide solution, and the suspension was placed in a reactor with a power of 2.3 kW, the reaction temperature was 68 ° C, the reaction time was 1.8 h, the reaction speed was 260 r / min, and the carrier complex solution was obtained after the reaction;

[0100] S4. Place the carrier complex solution prepared in S3 into a vacuum dryer with a power of 1.8 kW, the vacuum drying pressure is 0.3 MPa, the vacuum drying temperature is 57° C., and the vacuum drying time is 4 h. After vacuum drying, a carrier complex is obtained.

[0101] In step S1, the mass fraction of the 4-sulfonic acid calixarene in ultrapure water is 30%; in step S2, the mass fraction of the nano-calcium carbonate in anhydrous ethanol is 40%.

[0102] The preparation method of the protective composition specifically comprises the following steps:

[0103] L1. Dissolve stevioside and rosmarinic acid in ultrapure water, put into a 1.3 kW stirrer, stir at 24°C, stir for 12 min, stir at 110 r / min, mix well, and obtain a mixed solution;

[0104] L2. Dissolve albumin in ultrapure water, put it into a stirrer with a power of 1.3 kW, stir at a temperature of 22°C, stir for 16 min, stir at a speed of 150 r / min, and mix well to obtain an albumin solution;

[0105] L3. Put the mixed solution prepared by L1 into the albumin solution prepared by L2, with a stirring temperature of 22°C, a stirring time of 22 min, and a stirring speed of 160 r / min. After mixing evenly, put it into a reactor with a power of 2.3 kW with cysteine, and the reaction temperature was 80°C, the reaction time was 2.2 h, and the reaction speed was 240 r / min. After the reaction, put it into a vacuum freeze-nano spray dryer with a power of 2.5 kW, the vacuum degree was -0.05 MPa, the freeze-nano spray drying temperature was -40°C, the freeze-nano spray drying particle size was 100 nm, and the freeze-nano spray drying time was 2.6 h to obtain a protective composition.

[0106] In step L1, the mass fraction of stevioside in ultrapure water is 12%, and the mass fraction of rosmarinic acid in ultrapure water is 13%; in step L2, the mass fraction of albumin in ultrapure water is 4%.

[0107] This embodiment also provides a method for preparing an injection containing meropenem, which specifically comprises the following steps:

[0108] Step 1, weigh 225 parts by weight of chloroform-anhydrous ethanol and meropenem, carrier complex, and sodium carboxymethyl cellulose, put them into a stirrer with a power of 1.3 kW, stir at a temperature of 22° C., stir for 26 min, and stir at a speed of 130 r / min, fully dissolve them, and obtain a mixed solution containing meropenem;

[0109] Step 2: The meropenem-containing mixed solution prepared in step 1 was adjusted to a pH value of 8.2 using a 5 mol / L sodium carbonate solution, and then placed in a reactor with a power of 2.3 kW, with a reaction stirring rate of 1100 r / min, a reaction temperature of 75°C, and a reaction time of 75 min to obtain a drug-containing nanoparticle suspension after a precipitation reaction;

[0110] Step 3: Place the drug-containing nanoparticle suspension prepared in step 2 into a high-speed centrifuge with a power of 2.7 kW, the centrifugal speed is 12000 r / min, the centrifugal temperature is 2°C, the centrifugal time is 12 min, and after centrifugation, place it at 28°C for 1.2 h, and filter it using a sterile filter with a pore size of 100 nm to obtain drug-containing nanoparticles;

[0111] Step 4: Place the drug-containing nanoparticles prepared in step 3, the protective composition, 0.9% sodium chloride solution, and sterile water for injection into a 1.3 kW agitator at a stirring temperature of 22°C, a stirring time of 20 min, and a stirring speed of 110 r / min. After mixing, filter using a 0.22 mm sterile filter membrane to obtain an injection containing meropenem.

[0112] Example 5: This example provides an injection containing meropenem and a preparation method thereof. The injection containing meropenem comprises the following components in parts by weight:

[0113] 13 parts of meropenem, 29 parts of carrier complex, 22 parts of protective composition, 32 parts of 0.9% sodium chloride solution, 12 parts of sodium carboxymethyl cellulose, and 2500 parts of sterile water for injection.

[0114] The raw materials for preparing the carrier complex include the following components in parts by weight: 45 parts of 4-sulfonic acid calixarene and 55 parts of nano calcium carbonate; the raw materials for preparing the protective composition include the following components in parts by weight: 33 parts of stevioside, 38 parts of rosmarinic acid, 45 parts of albumin, and 32 parts of cysteine; the albumin was purchased from Sigma with a product number of A5503.

[0115] The method for preparing the carrier complex specifically comprises the following steps:

[0116] S1. Dissolve 4-sulfonic acid calixarene in ultrapure water, put into a stirrer with a power of 1.5 kW, stir at a temperature of 29° C., stir for 14 min, stir at a speed of 140 r / min, and stir evenly to obtain a 4-sulfonic acid calixarene solution;

[0117] S2, dispersing nano-calcium carbonate in anhydrous ethanol, placing in an ultrasonic stirrer with a power of 2.3 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 29° C., and a stirring time of 14 min to form a nano-calcium carbonate suspension;

[0118] S3, the nano calcium carbonate suspension prepared by S2 is placed in the 4-sulfonic acid calixarene solution prepared by S1, the stirring temperature is 29 ° C, the stirring time is 12 min, the stirring speed is 200 r / min, after mixing evenly, the pH is adjusted to 7.5 with a 30% mass fraction of sodium hydroxide solution, and the suspension is placed in a reactor with a power of 2.5 kW, the reaction temperature is 72 ° C, the reaction time is 2.3 h, the reaction speed is 280 r / min, and the carrier complex solution is obtained after the reaction;

[0119] S4. Put the carrier complex solution prepared in S3 into a vacuum dryer with a power of 2.1 kW, the vacuum drying pressure is 0.3 MPa, the vacuum drying temperature is 59° C., the vacuum drying time is 4 h, and after vacuum drying, a carrier complex is obtained.

[0120] In step S1, the mass fraction of the 4-sulfonic acid calixarene in ultrapure water is 45%; in step S2, the mass fraction of the nano-calcium carbonate in anhydrous ethanol is 55%.

[0121] The preparation method of the protective composition specifically comprises the following steps:

[0122] L1. Dissolve stevioside and rosmarinic acid in ultrapure water, put into a 1.5 kW stirrer, stir at 25°C, stir for 14 min, stir at 130 r / min, mix well, and obtain a mixed solution;

[0123] L2. Dissolve albumin in ultrapure water, put it into a stirrer with a power of 1.5 kW, stir at a temperature of 26°C, stir for 18 min, stir at a speed of 170 r / min, and mix well to obtain an albumin solution;

[0124] L3. Put the mixed solution prepared by L1 into the albumin solution prepared by L2, with a stirring temperature of 26°C, a stirring time of 24 min, and a stirring speed of 180 r / min. After mixing evenly, put it into a reactor with a power of 2.5 kW with cysteine, and the reaction temperature was 80°C, the reaction time was 2.4 h, and the reaction speed was 260 r / min. After the reaction, put it into a vacuum freeze-nano spray dryer with a power of 2.7 kW, the vacuum degree was -0.05 MPa, the freeze-nano spray drying temperature was -40°C, the freeze-nano spray drying particle size was 100 nm, and the freeze-nano spray drying time was 2.9 h to obtain a protective composition.

[0125] In step L1, the mass fraction of stevioside in ultrapure water is 14%, and the mass fraction of rosmarinic acid in ultrapure water is 17%; in step L2, the mass fraction of albumin in ultrapure water is 5%.

[0126] This embodiment also provides a method for preparing an injection containing meropenem, which specifically comprises the following steps:

[0127] Step 1, weigh 235 parts by weight of chloroform-anhydrous ethanol, meropenem, carrier complex, and sodium carboxymethyl cellulose, put them into a stirrer with a power of 1.5 kW, stir at a temperature of 26° C., stir for 29 min, and stir at a speed of 150 r / min, fully dissolve them, and obtain a mixed solution containing meropenem;

[0128] Step 2: The meropenem-containing mixed solution prepared in step 1 was adjusted to a pH value of 8.4 using a 5 mol / L sodium carbonate solution, and then placed in a reactor with a power of 2.5 kW, with a reaction stirring rate of 1300 r / min, a reaction temperature of 90°C, and a reaction time of 85 min to obtain a drug-containing nanoparticle suspension after a precipitation reaction;

[0129] Step 3, placing the drug-containing nanoparticle suspension prepared in step 2 into a high-speed centrifuge with a power of 2.9 kW, the centrifugal speed is 14000 r / min, the centrifugal temperature is 2°C, the centrifugal time is 14 min, and after centrifugation, it is placed at 28°C for 1.4 h, and filtered using a sterile filter with a pore size of 100 nm to obtain drug-containing nanoparticles;

[0130] Step 4: Place the drug-containing nanoparticles prepared in step 3, the protective composition, 0.9% sodium chloride solution, and sterile water for injection into a 1.5 kW stirrer at a stirring temperature of 27°C, a stirring time of 25 min, and a stirring speed of 130 r / min. After mixing, filter using a 0.22 mm sterile filter membrane to obtain an injection containing meropenem.

[0131] Comparative Example 1: This comparative example provides a meropenem injection and a preparation method thereof, which is different from Example 1 only in that the added components do not contain a carrier complex, and the remaining components, component contents, and method steps are the same as those in Example 1.

[0132] Comparative Example 2: This comparative example provides a meropenem injection and a preparation method thereof, which is different from Example 1 only in that the added components do not include a protective composition, and the remaining components, component contents, and method steps are the same as those in Example 1.

[0133] Experimental Example 1: Allergenicity test of injection containing meropenem.

[0134] The steps of the sensitization test for the meropenem-containing injection prepared in Examples 1-5 of the present invention are as follows:

[0135] (1) 1 mL of the meropenem injection prepared in Examples 1-5 was measured, diluted 200 times with a PBS buffer solution with a pH of 7.4, and used as samples of Example 1-5 groups; 1 mL of the meropenem injection prepared in Comparative Example 1-2 was measured, diluted 200 times with a PBS buffer solution with a pH of 7.4, and used as samples of the comparative group; 1 mL of ordinary meropenem injection (purchased from Sichuan Kelun Pharmaceutical Co., Ltd., prepared by mixing 0.5 g of meropenem with 100 mL of 0.9% sodium chloride injection) was measured as the CK control group, diluted 200 times with a PBS buffer solution with a pH of 7.4, and used as samples of the control group; the samples were added to the ELISA plate, 0.1 mL was added to each well, and incubated at 4°C overnight;

[0136] (2) Wash the plate 5 times with 250 mL / well of washing buffer each time, incubate at 28°C for 5 min, pat dry, add 200 mL of 5% bovine serum albumin to each well for blocking, incubate at 37°C for 2 h, and wash the plate 5 times;

[0137] (3) Add 100 mL / well of mixed serum from patients with meropenem allergy diluted 1:30 and incubate at 37°C for 1 h. After the reaction is complete, wash the plate 5 times.

[0138] (4) Add 200 mL / well of 1:5000 diluted biotin-labeled goat anti-human IgE, incubate at 37°C for 2 h, wash the plate 5 times, add 100 mL / well of substrate colorimetric solution, and develop at 37°C in the dark for 30 min. After development, add 50 mL / well of 2 mol / L sulfuric acid solution to terminate the reaction, and measure the absorbance (OD value) at a wavelength of 450 nm. Calculate the binding capacity of the experimental group samples with IgE according to the formula: IgE binding capacity (%) = OD experimental group / OD control group × 100%. The obtained data were statistically analyzed using IBM SPSS Statistics 22.0 software, and graphics were drawn using Origin 2022.

[0139] Result analysis:

[0140] Figure 1 This is a graph of the sensitization ability determination result described in Experimental Example 1 of the present invention. As shown in the figure, the binding ability of the meropenem injection containing meropenem described in Examples 1-5 with IgE antibodies decreased by 77.2%, 78.2%, 78.6%, 77.7%, and 78.3% respectively compared with the binding ability of the ordinary meropenem injection with IgE antibodies in the control group. The meropenem injection prepared in Comparative Example 1 does not contain a carrier complex, and the binding ability of the ordinary meropenem injection with IgE antibodies in the control group has not decreased. The binding ability of the meropenem injection prepared in Comparative Example 2 is reduced by 77.3% compared with the ordinary meropenem injection in the control group. It shows that the meropenem injection containing meropenem prepared by the present invention has strong stability, and the sulfonic acid group of sulfonic acid calixarene is used to form a coordination bond with the calcium ions on the surface of nano-calcium carbonate to achieve surface modification. The obtained carrier complex has a high specific surface area, strong adsorption capacity, and will not induce an immune response of the body. The body is not prone to allergies after injection.

[0141] Experimental Example 2: Irritation measurement test of injection containing meropenem.

[0142] The irritation test steps for the meropenem injection prepared in Examples 1-5 of the present invention on rats are as follows:

[0143] (1) 80 SD male rats, each weighing 220 g (purchased from Chengdu Dashuo Animal Co., Ltd.), were randomly divided into 8 groups of 10 rats. The rats were housed in separate cages, which were kept clean and dry at a temperature of 24°C and a humidity of 50%. The rats were fed with free access to food and water.

[0144] (2) After feeding for 10 days, the rats were fasted for 24 hours and injected with the meropenem injection prepared in Examples 1-5, once a day, 1.5 mL each time for 10 days. As the Example 1-5 group, the rats were injected with the meropenem injection prepared in Comparative Example 1-2, once a day, 1.5 mL each time for 10 days. As the comparative example group, the rats were injected with ordinary meropenem injection, once a day, 1.5 mL each time for 10 days as the CK control group. The diarrhea rate of the rats on the 10th day was observed and recorded, and the average value was taken. The diarrhea rate of the rats was calculated according to the formula: Rat diarrhea rate (%) = number of rats with diarrhea in each group / total number of rats in each group × 100%;

[0145] (3) Rats were killed by cervical dislocation, and their kidneys were separated. They were rinsed with 0.9% saline, and the surface moisture was dried with filter paper. The kidneys were weighed immediately. The kidney organ index (%) = kidney organ weight / rat body weight × 100%. An increase in the kidney organ index indicates organ congestion, edema, or hyperplasia, and a decrease in the kidney organ index indicates organ atrophy and other degenerative changes.

[0146] (4) The kidney tissues of rats in Example 1, Comparative Example 2 and CK control groups in step (3) were fixed in a 4% formaldehyde solution for 24 h, and then dehydrated in 50%, 70% and 90% ethanol solutions, respectively, for 1 h each time. The dehydrated kidney tissues were placed in a xylene solution twice, for 15 min each time, and then immersed in a paraffin solution twice, for 1 h each time. The immersed kidney tissues were sliced ​​to a thickness of 5 mm, dried, and stained in a HE staining solution for 10 min, washed with ultrapure water, sealed with neutral gum, and observed and recorded with an optical microscope.

[0147] Table 1. Rat irritation test table

[0148]

[0149] Result analysis: Figure 2 This is the staining image of the kidney tissue of the rats in the control group of Experimental Example 2 of the present invention, Figure 3 This is the staining picture of the kidney tissue of rats in the comparative example 2 described in the experimental example 2 of the present invention. Figure 4 This is the kidney tissue diagram of rats in Example 1 described in Experimental Example 2 of the present invention, as shown in FIG. Figure 2 , Figure 3 , Figure 4As shown in Table 1, the meropenem injection prepared by injection Examples 1-5 can significantly reduce the irritation to the kidney and gastrointestinal tract of rats, and effectively avoid diarrhea and kidney lesions. The control group injected with ordinary meropenem injection and the comparative example 2 group injected with meropenem injection not containing the protective composition, the rat kidney tissue showed microlesions and inflammation, the gap between the glomerulus and the renal capsule in the rat kidney was enlarged, and the renal organ index was significantly higher than that of the rats injected with the meropenem injection prepared by Examples 1-5, indicating that the protective combination contained in the meropenem injection of the present invention can effectively reduce the irritation of meropenem to the kidney and gastrointestinal tract.

[0150] Experimental Example 3: Test for determining the efficacy of an injection containing meropenem.

[0151] The steps of the drug efficacy determination test for the meropenem injection prepared in Examples 1-5 of the present invention are as follows:

[0152] (1) 80 SD male rats, each weighing 220 g (purchased from Chengdu Dashuo Animal Co., Ltd.), were randomly divided into 8 groups of 10 rats. The rats were housed in separate cages, which were kept clean and dry at a temperature of 24°C and a humidity of 50%. The rats were fed with free access to food and water.

[0153] (2) After 10 days of feeding, the rats were fasted for 24 h and anesthetized with 1% sodium pentobarbital (11 mg) by intraperitoneal injection. After anesthesia, the rats were injected intracranially with a concentration of 5×10 6 cfu / mL of Staphylococcus aureus 8325-4 solution, the dose was 5 mL, after the rats recovered, they were placed at room temperature and allowed to drink water and eat freely, thus obtaining meningitis model rats, which showed symptoms of slow reaction and convulsions;

[0154] (3) The meropenem injection prepared in Example 1-5 was used to inject the meningitis model rats prepared in step (2), once a day, 1.5 mL each time for 8 consecutive days as Example 1-5 group, the meropenem injection prepared in Comparative Example 1-2 was used to inject the meningitis model rats prepared in step (2), once a day, 1.5 mL each time for 8 consecutive days as Comparative Example 1-2 group, and the ordinary meropenem injection was used to inject the meningitis model rats prepared in step (2), once a day, 1.5 mL each time for 8 consecutive days as CK control group. The daily cure rate of rats in each group was calculated according to the formula and recorded, rat cure rate (%) = number of rats in each group with sluggish reaction and convulsion symptoms disappeared / number of rats in each group × 100%;

[0155] (4) Observe the recurrence of meningitis in the rats cured in step (3) every 10 days. Calculate the recurrence rate of rat meningitis according to the formula. Observe for 80 consecutive days and record the results. The recurrence rate of rat meningitis (%) = the number of rats in each group with sluggish reaction and convulsion symptoms / the number of rats in each group × 100%.

[0156] Table 2. Recurrence rate of meningitis in rats

[0157]

[0158] Result analysis: Figure 5 The result diagram of the cure of rats described in Experimental Example 3 of the present invention is shown in the figure. As shown in the figure, the meropenem injections described in Examples 1-5 were continuously injected into rats for 8 days, and it was observed that the cure rate of rats in Group 3 reached 100% on the 5th day after injection, the cure rate of rats in Groups 2, 4 and 5 reached 100% on the 6th day after injection, and the cure rate of rats in Group 1 reached 100% on the 7th day after injection. The meropenem injections described in Comparative Examples 1-2 were continuously injected into rats for 8 days, and it was observed that the cure rate of rats in Group 1 was 60% on the 8th day after injection, and the cure rate of rats in Group 2 reached 100% on the 8th day after injection. The cure rate of rats in the control group injected with ordinary meropenem injection was only 60% on the 8th day after injection. As shown in Table 2, every 10 The recurrence of meningitis in the cured rats in each group was observed once d. On the 80th day, the recurrence rates of meningitis in the rats injected with the meropenem injection prepared in Examples 1-5 were all 0%, the recurrence rate of meningitis in the rats in the comparative example 1 group injected with the meropenem injection not containing the carrier complex was 50% on the 80th day, the recurrence rate of meningitis in the rats in the comparative example 2 group injected with the meropenem injection not containing the protective composition was 0% on the 80th day, and the recurrence rate of meningitis in the rats in the control group injected with ordinary meropenem injection was 60% on the 80th day. This shows that the carrier complex in the meropenem injection prepared by the present invention has a high specific surface area and strong adsorption, and effectively improves the solubility and utilization rate of meropenem after efficiently adsorbing meropenem. The effective components in the injection have efficient drug loading, sustained release, fast efficacy, and can exert their effects for a long time without the need for multiple injections.

[0159] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

[0160] The present invention and its implementation methods are described above, which is not restrictive. The drawings are only one of the implementation methods of the present invention, and the actual application is not limited thereto. In short, if ordinary technicians in the field are inspired by it and design methods and embodiments similar to the technical solution without creativity without departing from the purpose of the invention, they should all fall within the protection scope of the present invention.

Claims

1. An injection containing meropenem, characterized in that: The meropenem injection comprises the following components in parts by weight: 10-13 parts of meropenem, 25-30 parts of carrier complex, 18-23 parts of protective composition, 25-35 parts of 0.9% sodium chloride solution, 10-12 parts of sodium carboxymethyl cellulose, and 2000-2600 parts of sterile water for injection; The raw materials for preparing the carrier complex include the following components in parts by weight: 30-50 parts of 4-sulfonic acid calixarene and 40-60 parts of nano calcium carbonate; The raw materials for preparing the protective composition include the following components in parts by weight: 25-35 parts of stevioside, 30-40 parts of rosmarinic acid, 40-46 parts of albumin, and 25-35 parts of cysteine; The method for preparing the carrier complex specifically comprises the following steps: S1, dissolving 4-sulfonic acid calixarene in ultrapure water, stirring evenly, to obtain a 4-sulfonic acid calixarene solution; S2, dispersing nano calcium carbonate in anhydrous ethanol, stirring the solution by ultrasonic wave to make it uniform, and obtaining a nano calcium carbonate suspension; S3, mixing the nano-calcium carbonate suspension prepared in S2 with the 4-sulfonic acid calixarene solution prepared in S1, adjusting the pH to 7.5 with a 30% by mass sodium hydroxide solution after mixing evenly, performing the reaction and drying under reduced pressure to obtain a carrier complex; The preparation method of the protective composition specifically comprises the following steps: L1, dissolving stevioside and rosmarinic acid in ultrapure water, and mixing well to obtain a mixed solution; L2. Dissolve albumin in ultrapure water, and stir to obtain an albumin solution; L3, putting the mixed solution prepared by L1 into the albumin solution prepared by L2, mixing well, adding cysteine ​​to react, and then vacuum freezing nano spray drying to obtain a protective composition.

2. The meropenem-containing injection according to claim 1, characterized in that: In step S1, the mass fraction of the 4-sulfonic acid calixarene in ultrapure water is 25%-50%.

3. The meropenem-containing injection according to claim 2, characterized in that: In step S2, the mass fraction of the nano-calcium carbonate in anhydrous ethanol is 33%-60%.

4. The meropenem-containing injection according to claim 3, characterized in that: In step L1, the mass fraction of stevioside in ultrapure water is 10%-15%, and the mass fraction of rosmarinic acid in ultrapure water is 12%-18%.

5. The meropenem-containing injection according to claim 4, characterized in that: In step L2, the mass fraction of albumin in ultrapure water is 4%-5%.

6. A method for preparing the meropenem injection according to any one of claims 1 to 5, characterized in that: The specific steps include: Step 1, weighing 220-240 parts by weight of chloroform-anhydrous ethanol, meropenem, carrier complex, and sodium carboxymethyl cellulose, and mixing them thoroughly to obtain a meropenem-containing mixed solution; Step 2: adjusting the pH of the meropenem-containing mixed solution prepared in step 1 to 8.0-8.5 using a 5 mol / L sodium carbonate solution, and performing a precipitation reaction to obtain a drug-containing nanoparticle suspension; Step 3: After centrifuging the drug-containing nanoparticle suspension prepared in step 2, filter it through a sterile filter with a pore size of 100 nm to obtain drug-containing nanoparticles; Step 4: Mix the drug-containing nanoparticles prepared in step 3 with the protective composition, 0.9% sodium chloride solution, and sterile water for injection, and filter using a 0.22 mm sterile filter membrane to obtain an injection containing meropenem.

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